This invention is directed to the field of compositions for use as skin whitening agents.
Exposure to the sun over time can induce many biochemical reactions in the skin. For example, exposure can lead to sunburn and tanning, which are immediate and well recognized. Other consequences of exposure to the sun are more subtle and accumulate over time. Often melanocytes can accumulate and the action of the enzyme tyrosinase is increased. These changes can result in the development of age spots and create an uneven, mottled skin tone. Unfortunately, many of the commercially available products in today""s market are either only marginally effective, or contain active agents that are unstable and lose their potency when incorporated into a final formula.
The ability to modify the expression of pigment content in the skin, to promote an even-looking skin tone and a more youthful appearance, is highly desired in today""s society. Many people desire to modify their skin tone, to reduce aging spots, melasma, etc., or for purely cosmetic reasons. In fact, in the Far East, a lighter skin tone is desirable and is associated with higher socio economic status.
Hyper-pigmentation in the skin is caused by the over expression or accumulation of melanin in the skin. As a result, the pathway involved in melanin production has been the target for many inhibitors so as to reduce the levels produced. One of the principal enzymes involved in the melanin pathway is tyrosinase, and there are many commonly used inhibitors of this enzyme. Unfortunately, there are many stability issues associated with the majority of these active agents when incorporated into aqueous systems. One of the most potent tyrosinase inhibitors, kojic acid, is prone to oxidation leading to breakdown and severe color changes in certain formulations. Ascorbic acid has also been used for its whitening properties and like kojic acid is prone to oxidation in aqueous systems. Indeed ascorbic acid is highly unstable in aqueous systems and degrades much more rapidly than most of the other whitening actives.
U.S. Pat. No. 3,812,251 to Mima et al., describes an aqueous composition containing ascorbic acid phosphate stabilized by the addition of boric acids and water-soluble salts.
Further, PCT Patent Application WO 99/07362 discloses a process for stabilizing levogyre ascorbic acid (LAA) by adding at least one compound linked to the LAA by hydrogen bridges. An LAA emulsion containing a least one hydrogen bonded compound is produced. However, WO ""362 describes compositions which are limited to use in solutions and serums. WO ""363 does not describe or suggest compositions which can be incorporated into cosmetic emulsions and similar formulations.
It would be desirable to those skilled in the art to realize a way of formulating a composition which can be effectively used as a topically applied skin whitening agent. In particular, identifying a composition that has improved stability and efficacy relative to those described in the prior art would be of significant commercial interest.
Applicants have now discovered stable compositions comprising tyrosinase inhibitors, which are useful in topically applied cosmetic and pharmaceutical formulations.
It is an object of the present invention to provide a composition of matter which will enhance or improve the appearance of skin by evening skin tone.
It is another object of the present invention to provide a composition of matter which includes a polyhydroxy or polycarboxy carboxylic acid, such as lactic acid; a polyhydroxy alkyl compound (such as glycerin); and two or more active agents which are useful as tyrosinase inhibitors and/or pigmentation reversing agents.
The invention is directed to stable, homogeneous compositions which are effective as skin whitening agents. The compositions of the invention comprise
(a) at least one alpha, beta or gamma substituted mono-, di or polyhydroxy or polycarboxy carboxylic acid;
(b) at least one mono-, di, tri or polyhydroxy alkyl compound; and one or more of
(c) an effective amount of an inhibitor of tyrosinase; and
(d) an effective amount of a pigmentation reversing reagent.
The invention may comprise one or more of any of the tyrosinase inhibitors or pigmentation reversing agents known in the art, and in particular may include one or more of the tyrosinase inhibitors pigmentation reversing agents further described herein.
In particular embodiments, the mono-, di or polyhydroxy or polycarboxy carboxylic acid is an alpha or beta hydroxy acid, such as lactic, glycolic, malic or citric acid. In particular embodiments, the mono-, di, tri or polyhydroxy alkyl compound is glycerin, sorbitol, mannitol, polyol, propylene glycol, ethylene glycol, butylene glycol, hexylene glycol and mixtures thereof.
The invention is also directed in part to methods of forming the stable, non-irritating compositions of the invention. Methods of the invention include coupling a hydroxy acid, a hydroxy alkyl compound, a tyrosinase inhibitor, and a pigmentation reversing agent, with a carboxylic acid activating agent to generate a homogeneous composition.
In another embodiment, methods of the invention include forming a stable, non-irritating composition having skin whitening properties, comprising the steps of forming a mixture of glycerin, a tyrosinase inhibitor, a pigmentation reversing agent, and lactic acid; heating the mixture and mixing until the mixture is clear and homogeneous.
The invention is also directed to methods of lightening the skin color of a human, or methods of evening the skin tone of a human, comprising contacting the skin of a human with a composition of the invention.